Several human conditions are characterized by distinctive lipid compositions of tissues, cells, membranes, and extracellular regions or structures. For example, in atherosclerosis, cholesterol (unesterified, esterified, and oxidized forms) and other lipids accumulate in cells and in extracellular areas of the arterial wall and elsewhere. These lipids have potentially harmful biologic effects, for example, by changing cellular functions, including gene expression, and by narrowing the vessel lumen, obstructing the flow of blood. Removal of these lipids would provide numerous substantial benefits. Moreover, cells, membranes, tissues, and extracellular structures will benefit in general from compositional alterations that include increasing resistance to oxidation and oxidative damage, such as by increasing the content and types of anti-oxidants, removing oxidized material, and increasing the content of material that is resistant to oxidation. In aging, cells have been shown to accumulate sphingomyelin and cholesterol, which alter cellular functions. These functions can be restored in vitro by removal of these lipids and replacement with phospholipid from liposomes. A major obstacle to performing similar lipid alterations in vivo has been disposition of the lipids mobilized from tissues, cells, extracellular areas, and membranes. Natural (e.g., high-density lipoproteins) and synthetic (e.g., small liposomes) particles that could mobilize peripheral tissue lipids have a substantial disadvantage: they deliver their lipids to the liver in a manner that disturbs hepatic cholesterol homeostasis, resulting in elevations in plasma concentrations of harmful lipoproteins, such as low-density lipoprotein (LDL), a major atherogenic lipoprotein. There exist a need for a better method to manipulate the lipid content and composition of peripheral tissues, cells, membranes, and extracellular regions in vivo.
The intravenous administration of cholesterol-poor phospholipid vesicles (liposomes) or other particles that transport cholesterol and other exchangeable material from lipoproteins and peripheral tissues, including atherosclerotic arterial lesions, to the liver produces substantial derangements of hepatic cholesterol homeostasis, such as enhanced hepatic secretion of apolipoprotein-B, and suppression of hepatic LDL receptors. The hepatic derangements lead to increase plasma concentrations of LDL and other atherogenic lipoproteins. Increased concentrations of LDL or other atherogenic lipoproteins will accelerate, not retard, the development of vascular complications. Deranged hepatic cholesterol homeostasis can also be manifested by abnormal regulation of genes, such as a gene for the LDL receptor, a gene for HMG-CoA reductase, a gene for cholesterol 7-alpha hydroxylase, and a gene regulating a function involved in cholesterol homeostasis. There exists a need for methods and compounds that can produce a removal of cholesterol and other exchangeable material, from peripheral cells, tissues, organs, and extracellular regions, and that can produce a delivery of material, such as phospholipids, to cells, tissues, or organs, extracellular regions without harmfully disrupting hepatic cholesterol homeostasis and plasma concentrations of atherogenic lipoproteins.
By way of example, atherosclerosis, a major killer in Western countries, is characterized by the accumulation of cholesterol and cholesteryl ester in cells and in extracellular areas of the arterial wall and elsewhere. There exists a need for a better method to manipulate the lipid content and composition of peripheral tissues, cells, membranes, and extracellular regions in vivo. There further exists a need for methods or compounds that can produce removal of cholesterol from cellular and extracellular regions of arteries, but without provoking a rise in the plasma concentration of LDL.
The invention described herein provides methods and compositions related to the removal of cholesterol from arteries, whole controlling plasma concentrations of LDL. The present invention addresses these needs so that diseases and detrimental medical conditions can be treated, controlled or eliminated.
This invention provides methods and compositions that relate to the xe2x80x9creversexe2x80x9d transport of lipids and other exchangeable material from peripheral tissues to the liver in vivo while controlling plasma LDL concentrations. There exists a need for a method of, treatment, and a pharmaceutical composition for forcing the reverse transport of lipids from peripheral tissues to the liver in vivo while controlling plasma LDL concentrations; of regulating hepatic parenchymal cell cholesterol content and metabolism in a cell having at least one gene selected from the group consisting of a gene for an LDL receptor, a gene for HMG-CoA reductase, a gene for cholesterol 7-alpha-hydroxylase, and a gene regulating a function involved in cholesterol homeostasis; and, homeostasis thereof; suppressing hepatic expression of a cholesterol ester transfer protein gene in vivo, whereby plasma LDL and HDL are controlled as a result of the administration; suppressing the rise in plasma LDL concentrations after administration of an agent having small acceptors of cholesterol or other lipids; of diagnosing a side-effect of reverse transport of cholesterol from peripheral tissues to the liver in vivo accompanying parenteral administration of a multiplicity of large liposomes and small liposomes during a treatment period, whereby a side effect of administration of the liposomes is diagnosed and effectively regulated; and, diagnosing and treating a side-effect of reverse transport of lipids from peripheral tissues to the liver in vivo accompanying parenteral administration of a multiplicity of large liposomes and small liposomes during a treatment period. There further exists a need for a system in which patients will have a decreased risk of developing atherosclerosis and/or cellular changes from aging; an improved method of reducing the lipid content of lesions.
The invention described herein provides methods and compositions related to the removal of cholesterol and other exchangeable material from peripheral tissues, and otherwise altering peripheral tissue lipids, while controlling plasma concentrations of LDL and other atherogenic lipoproteins and avoiding harmful disruptions of hepatic cholesterol homeostasis. Specific genes in both the peripheral tissues and in the liver are controlled by these methods and compositions. There exists a need for better methods to manipulate the lipid content and composition of peripheral tissues, cells, membranes, and extracellular regions in vivo, particularly in regard to diseases and processes involving oxidation and oxidative damage. Moreover, currently available artificial particles for intravenous administration contain significant amounts of oxidized material (Helbock et al. Pediatrics 91:83-87, 1993), which contributes to their unsuitability for these purposes.
There further exists a need for methods or compounds that can produce a removal of cholesterol and other exchangeable material, including oxidized materials, from peripheral cells, tissues, organs, and extracellular regions, and that can produce a delivery of anti-oxidants to cells, tissues, organs, and extracellular regions, but without harmfully disrupting hepatic cholesterol homeostasis, including hepatic gene expression and regulation.
The invention described herein provides methods and compositions related to the removal of cholesterol and other exchangeable material from peripheral tissues, and otherwise altering peripheral tissue composition, to reduce or avoid oxidation and its effects and products, while controlling plasma concentrations of LDL and other atherogenic lipoproteins and avoiding harmful disruption of hepatic cholesterol homeostasis. It is an object of the invention of the present invention to solve the problems articulated above and other problems in the art.
Renal failure, both acute and chronic, is a major health problem. Current treatments for these conditions include hemodialysis, peritoneal dialysis, rectal dialysis, renal transplantation, and treatment of the underlying renal disease when possible. A major, widely recognized drawback to all methods of treatment of renal failure is accelerated atherosclerosis, which leads to heart attacks, strokes, claudication, and many other complications. Renal patients also undergo accelerated aging. There exists a need to reduce or eliminate atherosclerosis in patients with renal failure and reduce the rate of aging. These specific complications are treated with lipid-lowering drugs, LDL apheresis, angioplasty, coronary bypass surgery, carotid endarterectomy, other vascular reconstructive surgery, heart transplantation, and restoration of renal function when possible. Nevertheless, these methods are at best only partially effective and are often extremely invasive. There exists a need for a simple, effective, non-invasive or minimally invasive approach to reduce atherosclerosis or slow its development in patients with renal disease.
The intravenous administration of cholesterol-poor phospholipid vesicles (liposomes) or other particles to transport cholesterol from peripheral tissues, including atherosclerotic arterial lesions, to the liver produces substantial derangements in hepatic cholesterol homeostasis, such as enhanced hepatic secretion of apolipoprotein-B, the major protein of atherogenic lipoproteins, and suppression of hepatic LDL receptors (see, for example, Spady et al. J. Lipid Res. 26:465-472, 1985; Williams et al. Proc. Natl. Acad. Sci. USA 85:242-246, 1988; Williams et al. J. Biol. Chem. 265:16741-16744, 1990; Dixon and Ginsberg J. Lipid Res. 34:167-179, 1993; Tanka et al. Atherosclerosis 114:73-82, 1995; and citations therein). The hepatic derangements lead to increased plasma concentrations of LDL and other atherogenic lipoproteins. Increased concentrations of LDL or other atherogenic lipoprotein will accelerate, not retard, the development of vascular complications. Deranged hepatic cholesterol homeostasis can also be manifested by abnormal regulation of other genes, such as a gene for the LDL receptor, a gent for HMG-CoA reductase, a gender for cholesterol 7-alpha hydroxylade, and a gene regulating a function involved in cholesterol homeostasis. There exists a need for methods or compounds that can produce a removal of cholesterol and other exchangable material from peripheral cells, tissues, organs, and extracellular regions, but without harmfully disrupting hepatic cholesterol homeostasis.
The invention described herein provides methods a compositions related to the removal of cholesterol and other lipids from peripheral tissues, and otherwise altering peripheral tissue lipids, in patients with renal disease, while controlling plasma concentrations of LDL and other atherogenic lipoproteins and avoiding harmful disruptions of hepatic cholesterol homeostasis.
The present invention provides pharmaceutical compositions and methods useful for the treatment of atherosclerosis. More particularly, the compositions generally comprise liposomes having an average diameter of about 100-150 nanometers and a pharmaceutically acceptable carrier. The methods generally comprise administering such compositions.
Atherosclerosis is the leading cause of death in the United States. Atherosclerosis is the formation of plaques in arterial walls that can occlude the vessel lumen and obstruct blood flow through the vessel. Morbidity and mortality generally occur through end organ damage and organ dysfunction resulting from ischemia. The most common forms of ischemia that end in organ damage are myocardial infarction and cerebrovascular accidents. Disability or death often result from these vascular events. There exists a need in the art to treat these types of ischemia, and it is an object of the invention to treat different types of ischemia.
Even atherosclerosis-related ischemia that does not permanently injure myocardium is responsible for significant morbidity in the form of angina pectoris and congestive heart failure. Other organs, such as the kidneys, the intestines, and the spinal cord, may also be injured by atherosclerotic occlusions. Further, in diseases such as aortic aneurysms, atherosclerotic arteries may cause clinical symptoms independent of end organ dysfunction.
Arteriosclerotic lesions are plaques that form by accumulation of cholesterol, cholesterol esters, and phosphplipids and proliferation of smooth muscle cells in the intima of major arteries. Lipid contributes a major portion of the plaque volume (generally 30-65% dry weight). Small, Arteriosclerosis, 8:103-129 (1988). In fact, the risk of developing arteriosclerosis is directly related to the concentration of certain forms of plasma cholesterol. Lipids, including cholesterol, are generally insoluble in aqueous plasma. Plasma lipids are carried by soluble lipoprotein complexes. These lipoprotein complexes consist of an inner core of non-polar lipids (cholesteryl esters and triglycerides) and an surface layer of hydrophilic proteins and polar lipids (phospholipids and non-esterified cholesterol). Different proteins are present in the surface coat of different lipoprotein complexes (lipoproteins). The different lipoproteins perform different functions in lipid metabolism.
Five classes of lipoproteins are known. Some lipoproteins carry triglycerides and cholesterol from the liver to peripheral tissues while others transport lipids to the liver. Cholesterol may be metabolized in the liver to bile salts that are excreted, thus lowering total body cholesterol. Two lipoproteins, low density lipoproteins (LDL) and high density lipoproteins (HDL), have a high degree of association with the development of atherosclerosis. LDL has a high cholesterol concentration, delivers lipids to cells of peripheral tissues, and is associated with a high risk of atherosclerosis. HDL also has a relatively high cholesterol concentration, but carries lipids to the liver for metabolism into bile salts and is associated with decreasing the risk of developing atherosclerosis.
Cholesterol metabolism and homeostasis is the result of a complex equilibrium between free sterol in the cell and in plasma. Phillips et. al., Biochim. Biophys. Acta, 906:223 276 (1987). Delivery of cholesterol to cells occurs via the receptor-mediated LDL pathway and by passive exchange of sterol between plasma membranes and lipoproteins. Only tissues that produce steroid hormones and bile acids can metabolize cholesterol. In order to prevent accumulation of excess free sterol in remaining peripheral tissues there is a reverse transport of cholesterol from plasma membranes into HDL and lipoprotein-like particles. HDL transports excess cholesterol to the liver where it can either be processed into bile salts for excretion or incorporated into very low density lipoproteins (VLDL) to re-enter the lipoprotein pool.
The passive exchange of cholesterol between cells and lipoproteins occurs via the diffusion of sterol molecules across the aqueous space. Phillips et al., jupra, and Schroeder et al., Exp. Biol. Med., 196:235-252 (1991). Net cellular efflux: occurs if the chemical potential of free cholesterol is lower in the plasma than in the cells so that sterol leaves the membrane following its activity gradient.
Under these conditions, it has been shown that cholesterol ester-loaded cells, which are morphologically characteristic of early atherosclerotic lesions, not only lose cholesterol, but promote ester hydrolysis, resulting in the reduction of intracellular deposits of this lipid. Small, Arteriosclerosis, 8:103-129 (1988). Moreover as mentioned above, there is epidemiological evidence that conditions which might be expected to enhance reverse cholesterol transport (low plasma cholesterol concentrations, or increased HDL concentrations) are correlated with reduced risk of premature atherosclerosis and may give rise to plaque regression.
Characteristically, plaques are associated with ulceration of the vessel intima. The lipid-containing plaques grow in the ulcerations projecting friable masses into the arterial lumen. The plaques may also injure and weaken the smooth muscle media of the vessel. As plaque formation progresses, more central regions of the plaques are shielded from the circulation. Extensive plaque formation also cause concentric constriction of the vessel at the plaque site.
Presently, the most effective treatment of atherosclerosis is prevention. There is evidence that the progression and accumulation of lipids in lesions can be halted when plasma LDL concentrations are kept to near normal levels. Reynolds, Circulation, 79:1146-1148 (1989). Current preventive management of atherosclerotic disease has focused on the use of drugs in conjunction with dietary restrictions to regulate plasma cholesterol levels. Moreover, antioxidant therapies which suppress the formation and uptake of modified LDL particles by the cells of the arterial wall are also proving beneficial. Chisolm, Clin. Cardiol, 14:25-30 (1991).
However, while hypocholesterolemic drugs induce favorable plasma cholesterol changes which appear to slow the progression of atherosclerosis, they do hot generally induce conditions that promote the efflux and removal of atheroma cholesterol. Clearly, in order to achieve significant regression of atheroma and lessen lumen obstruction, these space occupying lipids must be mobilized. Present evidence suggests that processes which stimulate the efflux of extrahepatic cell cholesterol and transport it to the liver for excretion, reverse cholesterol transport (RCT), are important events in the prevention of atherosclerosis. Gwynne, Clin. Cardiol., 14:17-24 (1991).
Current therapeutic modalities of arteriosclerosis are generally divided into surgical and medical management. Surgical therapy may entail vascular graft procedures to bypass regions of occlusion (e.g., coronary artery bypass grafting), removal of occluding plaques from the arterial wall (e.g., carotid endarterectomy), or percutaneously cracking the plaques (e.g., balloon angioplasty). Surgical therapies carry significant risk and only treat isolated lesions.
Atherosclerotic plaques downstream from the treated lesion may continue to obstruct blood flow. Surgical therapies also do not limit the progression of atherosclerosis and are associated with the late complication of restenosis. Medical therapy is directed to reducing other risk factors related to vascular disease (e.g., smoking, diabetes, and hypertension) and lowering forms of serum cholesterol that are associated with the development of atherosclerosis as described above. While medical therapies may slow the progression of plaqye formation, plaque regression is relatively rare. Therefore, symptomatic atherosclerosis often requires both surgical and medical treatment.
Paradoxically, intravenous infusion of phospholipids and liposomes has been shown to produce regression of atherosclerotic plaques although serum lipid levels are transiently elevated. Williams et al., Perspect. Biol. Med., 27:417-431 (1984). In some instances, however, cholesterol associated with development and progression of atherosclerosis may increase following liposome administration.
Previous studies investigating phospholipid-induced mobilization of cholesterol in vivo have employed multilamellar or sonicated liposome vesicles. Liposome size is a key characteristic in clearance kinetics and is one of several reasons why sonicated vesicles have been expected to represent the bilayer structure best suited to enhance reverse cholesterol transport. Sonication reduces multilamellar vesicles (MLV) to xe2x80x98limit sizexe2x80x99 vesicles. These systems exhibit the minimum radius of curvature that can be adopted by the bilayer configuration without disruption. For example, the minimum size egg phosphatidyl choline liposome that can be generated is typically about 30-nm diameter, often classified as a small unilamellar vesicle (SUV). For a given liposome composition, it is generally assumed that the smaller the particle diameter the greater the circulation half-life (Gregoriadis and Senior, Life SO, 113:183-192 (1986)). Consequently, it was expected that SUV composed of phosphatidyl choline would circulate longer than larger liposomes, and therefore mobilize more cholesterol.
Furthermore, packing constraints experienced by phospholipids in SUV, (due to the acute radius of curvature) gives rise to an instability that can result in fusion, Hope et al., Chem. Phys. Livids, 40:89-107 (1986), as well as an increased tendency to assimilate with lipoproteins. See, e.g., Scherphof et al., Biochem. Biophys. Acta, 542:296-307 (1978) and Krupp et al., Biochem. Biophys. Acta, 72:1251-1258 (1976). Therefore, it was expected that SUV would produce a greater number of HDL-like particles, thus promoting efflux of sterol from peripheral tissues supporting this expectation, liposomes having diameters of 50-80 nm have been reported to optimize sterol mobilization and plaque regression. European Patent Publication No.-0461559A2.
What is needed in the art is a medical treatment for atherosclerosis that not only will slow progression of lesions, but also predictably cause regression and shrinkage of established plaques. Such a treatment should provide the optimal rate of cholesterol removal (and, hence shrinkage) from plaques.
The present invention fulfills these and other related needs.
The present invention provides a pharmaceutical composition, devices, modes of operation of devices, kit, and method of forcing the reverse transport of cholesterol from peripheral tissues to the liver in vivo while controlling plasma LDL concentrations. A method described above includes the step of administering a therapeutically effective amount of a multiplicity of large liposomes comprised of phospholipids substantially free of sterol for a treatment period. A method described above optionally includes the step of periodically assaying plasma LDL concentrations with an assay during the treatment period to assess plasma atherogenic lipoprotein concentrations and obtain an atherogenic lipoprotein profile, and adjusting the administration in response to the profile. The large liposomes are dimensioned larger than fenestrations of an endothelial layer lining hepatic sinusoids in the liver so that the liposomes are too large to readily penetrate the fenestrations. The therapeutically effective amounts are in the range of about 10 mg to about 1600 mg phospholipid per kg body weight per dose. A pharmaceutical composition and related kit for mobilizing peripheral cholesterol and sphingomyelin that enters the liver of a subject consisting essentially of liposomes of a size and shape larger than fenestrations of an endothelial layer lining hepatic sinusoids in the liver is also provided.
The present invention provides a pharmaceutical composition consisting essentially of large liposomes comprised of phospholipids substantially free of sterol. The composition forces the reverse transport of cholesterol from peripheral tissues to the liver in vivo. The invention further provides a method of treating atherosclerosis in a subject comprising the step of administering a liposome composition to the subject. The liposome composition is selected from the group consisting of unilamellar liposomes and multilamellar liposomes and the liposomes have an average diameter of about 50-150 nanometers. LDL levels in the subject do not increase with utilization of a method described above.
The invention also provides a method of controlling cholesterol metabolism in hepatic parenchymal cells in a subject in vivo through cellxe2x80x94cell communication from Kupffer cells to the parenchymal cells. A method described above includes the step of administering a liposome composition to a subject. The liposome composition is selected from the group consisting of large unilamellar liposomes and large multilamellar liposomes, and the liposomes having an average diameter of about 50-150 nanometers. Similarly, LDL levels in the subject do not increase. In variants, the liposome composition is given periodically, given more than once, or given in repeated doses.
The liposomes have diameters larger than about 50 nm, diameters larger than about 80 nm, and diameters larger than about 100 nm in different variants. Administration is selected from the group of parenteral administration, intravenous administration, intra-arterial administration, intramuscular administration, subcutaneous administration, transdermal administration, intraperitoneal administration, intrathecal administration, via lymphatics, intravascular administration, including administration into capillaries and arteriovenous shunts, rectal administration, administration via a chronically indwelling catheter, and administration via an acutely placed catheter, and given in about 10 to about 1600 mg/kg/dose of the liposome composition. The liposomes are phospholipids selected from the group consisting of phosphatidyl choline, phosphatidyl glycerol, palmitoyl-oleoyl phosphatidyl choline, combinations thereof, and derivatives thereof.
The present invention provides an improved mode of operation of an apparatus for angioplasty or cardiac catheterization, apparatus for angioplasty and cardiac catheterization, and method of angioplasty or cardiac catheterization. The improved mode of operation includes a mode of operation involving the administration of a therapeutically effective amount of a lipid acceptor during angioplasty or cardiac catheterization of a subject with the apparatus or component thereof. The lipid acceptor is selected from the group consisting of a large liposome comprised of phospholipids substantially free of sterol and small acceptors. The effective period of time is in the range of about less than 1 minute to about two years from the time of the angioplasty or cardiac catheterization. The improved angioplasty or cardiac catheterization apparatus includes means for administering a therapeutically effective amount of a lipid acceptor, and optional co-administration means for administering the lipid acceptor and a diagnostic agent. The improved mode of operating an angioplasty or cardiac catheterization apparatus includes administering a therapeutically effective amount of a lipid acceptor from the apparatus or component thereof into a vessel of a subject by administration means disposed on the apparatus. The invention further provides a method of diagnosing a side-effect of reverse transport of cholesterol from peripheral tissues to the liver in vivo accompanying parenteral administration of a multiplicity of large liposomes and small liposomes during a treatment period. A method described above includes the step of periodically assaying plasma atherogenic lipoprotein concentrations with an assay to obtain an assayed atherogenic lipoprotein concentration. The objects and features of the present invention other than those specifically set forth above, will become apparent in the detailed description of the invention.
A method of regulating cholesterol related genes, enzymes and other compounds, pharmaceutical compositions and a kit related thereto are provided. Exemplary genes that are regulated include a gene for an LDL receptor, a gene for HMG-CoA reductase, a gene for cholesterol 7-alpha-hydroxylase, and a gene regulating a function involved in cholesterol homeostasis. A method described above comprises the step of parenterally administering a therapeutically effective amount of a lipid acceptor. The lipid acceptor in one variant includes a multiplicity of large liposomes comprised of phospholipids substantially free of sterol during a treatment period. A method described above includes the steps of periodically assaying plasma LDL concentrations with an assay during a period of time to assess the plasma LDL and to obtain an LDL profile, and adjusting the parenteral administration in response to the LDL profile. A method described above further includes the step of enhancing tissue penetration of a cholesterol acceptor and enhancing extraction of tissue cholesterol and other exchangeable material with co-administration of an effective amount of a compound selected from the group consisting of a small acceptor of cholesterol, an amphipathic compound, and a drug that increases endogenous small acceptors of cholesterol.
Generally the compositions described herein include large liposomes of a size and shape larger than fenestrations of an endothelial layer lining hepatic sinusoids in the liver, whereby the liposomes are too large to readily penetrate the fenestrations. Therapeutically effective amounts of the compositions include in the range of 10 mg to 1600 mg phospholipid per kg body weight per dose. The large liposomes are selected from the group consisting of uni-lamellar liposomes and multi-lamellar liposomes. In variants, the liposomes have diameters larger than about 50 NM, diameters larger than about 80 NM, and diameters larger than about 100 NM.
The present invention provides compositions for, a method of suppressing the rise in plasma concentrations of atherogenic lipoproteins after administration of an agent having small acceptors of cholesterol, other lipids or compounds. A method described above includes the step of co-administering an effective amount of a multiplicity of an agent having large liposomes that include phospholipids substantially free of sterol with the administration of the agent having the small acceptors. The atherogenic lipoproteins include LDL, VLDL, IDL, xcex2-VLDL, Lp(a), a lipoprotein containing apolipoprotein-B, oxidized lipoproteins, and modified lipoproteins. The agent having small acceptors consists essentially of small acceptors and in which the agent having large liposomes consists essentially of large liposomes. In a variant, co-administration of the agent having large liposomes is simultaneous with the administration of the agent having small acceptors. Optionally, co-administration of the agent having large liposomes is separated in time from the administration of the agent having small acceptors by an effective time period. An improved pharmaceutical composition for reducing the size of arterial lesions that enters the liver of a subject is also provided the improvement comprises an anti-oxidant and derivatives thereof. The invention also provides an improved mode of operation of liposomes utilizing the improvements described herein.
The present invention further provides various methods, systems and compositions for forcing the reverse transport of cholesterol from peripheral tissues to the liver in vivo while controlling plasma LDL concentrations, and other significant components of living biological systems. A method described above comprises the step of parenterally administering a therapeutically effective amount of a multiplicity of large liposomes comprised of phospholipids substantially free of sterol for a treatment period whereby the liposomes pick-up the cholesterol during the treatment period. A method described above optionally includes the step of periodically assaying plasma LDL concentrations with an assay during the treatment period to assess the plasma LDL concentrations and obtain an LDL profile, and adjusting the parenteral administration in response to the LDL profile.
Exemplary assays are selected from the group consisting of an assay of plasma esterified cholesterol, an assay of plasma apolipoprotein-B, a gel filtration assay of plasma, an ultracentrifugal assay of plasma, a precipitation assay of plasma, and an immuno turbidometric assay of plasma.
A method described aboves optionally include the step of enhancing tissue penetration of a cholesterol acceptor by co-administration of an effective amount of a compound, the compound selected from the group consisting of a small acceptor of cholesterol and a drug that increases endogenous small acceptors of cholesterol. The small acceptor is selected from the group consisting of a high-density lipoprotein, a phospholipid protein complex having a group selected from the group consisting of apoA-I, apoA-II, apoA-IV, apoE, synthetic fragments thereof, natural fragments thereof, an amphipathic protein, and an amphipathic peptide, the protein substantially free of phospholipid, small phospholipid liposomes, and a small cholesterol acceptor. This includes an agent that raises physiologic HDL concentrations, the agent selected from the group consisting of nicotinic acid, ethanol, a fibric acid, a cholesterol synthesis inhibitor, a drug that increases HDL concentrations, and derivatives thereof. The invention further provides a method of, and composition for regulating hepatic parenchymal cell cholesterol content and gene expression by the steps described herein.
The present invention provides an improved dialysis apparatus for the treatment of a subject, improved mode of operation of a dialysis apparatus and improved method of dialysis. The improvement includes means for and a mode of operation for administering a therapeutically effective amount of a lipid acceptor during the treatment of a subject, and actuation of the means during operation of the dialysis apparatus. The lipid acceptor is selected from the group consisting of a multiplicity of large liposomes comprised of phospholipids substantially free of sterol and small acceptors. The means for administering the agent is selected from the group consisting of means for extracorporeal administration and means for intracorporal administration. The dialysis includes hemodialysis, peritoneal dialysis, and rectal dialysis, and the agent is added directly to blood or blood plasma of a subject in one variant.
Liposome compositions utilized herein also pick up and are useful in removing undesirable components in addition to cholesterol which improves the dialysis. Accordingly, an assay of the undesirable components, which may include lipids and other exchangeable material, is used to determine the effectiveness of the treatment. A method described above, mode of operation and apparatus provide for the control of plasma LDL concentrations, plasma concentrations of atherogenic lipoproteins and hepatic cholesterol homeostasis.
It is an object of the present invention to provide for better methods to manipulate the lipid content and composition of peripheral tissues, cells, membranes, and extracellular regions in vivo, particularly in regard to diseases and processes involving oxidation and oxidative damage. It is a further object of the present invention to provide for methods or compounds that can produce a removal of cholesterol and other exchangeable material, including oxidized materials, from peripheral cells, tissues, organs, and extracellular regions, and that can produce a delivery of anti-oxidants to cells, tissues, organs, and extracellular regions, but without harmfully disrupting hepatic cholesterol homeostasis, including hepatic gene expression and regulation.
It is an object of the invention to provide better methods to manipulate the lipid content and composition of peripheral tissues, cells, membranes, and extracellular regions in vivo.
It is a further object of the invention to regulate and control deranged hepatic cholesterol homeostasis as manifested by abnormal regulation of genes, such as a gene for the LDL receptor, ax gene for HMG-CoA reductase, a gene for cholesterol 7-alpha hydroxylase, and a gene regulating a function involved in removal of cholesterol and other exchangeable material from peripheral cells, tissues, organs, and extracellular regions, but without harmfully disrupting hepatic cholesterol homeostasis, including hepatic gene expression and regulation.
It is an object of the invention to provide a simple, effective, non-invasive or minimally invasive approach, method, device, and mode of operation of the device to reduce re-stenosis or slow its development in patients who undergo mechanical or surgical revascularization procedures.
It is a further object of the invention to provide a method, device, and mode of operation of a device to manipulate the lipid content and composition of the arterial wall before, during, and after revascularization procedures, to reduce re-stenosis. It is yet a further object of the invention to provide for a method to change LDL composition and size.
It is yet another object of the invention to provide a method, compound, device and mode of operation of a device that can produce a removal of cholesterol and other exchangeable material from peripheral cells, tissues, organs, and extracellular regions without harmfully disrupting hepatic cholesterol homeostasis.
It is an object of the invention to provide for better methods to manipulate the lipid content and composition of peripheral tissues, cells, membranes, and extracellular regions in vivo.
It is a further object of the invention to provide for methods and compounds that can produce removal of cholesterol from cellular and extracellular regions of arteries, but without provoking a rise in the plasma concentration of LDL.
It is an object of the present invention to provide a better method to manipulate the lipid content and composition of peripheral tissues, cells, membranes, and extracellular regions in vivo.
It is a further object of the invention to provide methods or compounds that can produce a removal of cholesterol and other exchangeable material, from peripheral cells, tissues, organs, and extracellular regions, and that can produce a delivery of material, such as phospholipids, to cells, tissues, or organs, extracellular regions, but without harmfully disrupting hepatic cholesterol homeostasis and plasma concentrations of atherogenic lipoproteins.
In one variant, the present invention provides pharmaceutical compositions consisting essentially of unilamellar liposomes having an average diameter of about 100-150 nanometers, which liposomes are not bound to a drug; and a pharmaceutically acceptable carrier. These liposomes optimize cholesterol efflux from atherosclerotic plaques. The liposomes may be bound to an apoprotein, typically apoprotein A1 or A2. The liposomes often contain at least one phospholipid, such as phosphatidyl choline or phosphatidylglycerol. Liposomes having diameters of about 125 nm are preferred.
Also provided are methods for treating atherosclerosis employing the pharmaceutical compositions of the present invention. The compositions are administered to animals having atherosclerosis often, the compositions will be serially administered over a period of time. Generally, the compositions will be administered parenterally, usually intravenously. The methods may be employed therapeutically or prophylactically. The methods of the present invention are also useful for treatment of hypoalphalipoproteinemia and hyperlipidemias.
The objects and features of the present invention, other than those specifically set forth above, will become apparent in the detailed description of the invention set forth below.